The KOR is a type of opioid receptor dat binds de opioid peptidedynorphin as de primary endogenous wigand (substrate naturawwy occurring in de body).[7] In addition to dynorphin, a variety of naturaw awkawoids, terpenes and oder syndetic wigands bind to de receptor. The KOR may provide a naturaw addiction controw mechanism, and derefore, drugs dat target dis receptor may have derapeutic potentiaw in de treatment of addiction, uh-hah-hah-hah.

There is evidence dat distribution and/or function of dis receptor may differ between sexes.[8][9][10]

Based on receptor binding studies, dree variants of de KOR designated κ1, κ2, and κ3 have been characterized.[13][14] However, onwy one cDNA cwone has been identified,[15] hence dese receptor subtypes wikewy arise from interaction of one KOR protein wif oder membrane associated proteins.[16]

The cwaustrum is de region of de brain in which de KOR is most densewy expressed.[19][20][21] It has been proposed dat dis area, based on its structure and connectivity, has "a rowe in coordinating a set of diverse brain functions", and de cwaustrum has been ewucidated as pwaying a cruciaw rowe in consciousness.[20][21] As exampwes, wesions of de cwaustrum in humans are associated wif disruption of consciousness and cognition, and ewectricaw stimuwation of de area between de insuwa and de cwaustrum has been found to produce an immediate woss of consciousness in humans awong wif recovery of consciousness upon cessation of de stimuwation, uh-hah-hah-hah.[21][22] On de basis of de preceding knowwedge, it has been proposed dat inhibition of de cwaustrum (as weww as, "additionawwy, de deep wayers of de cortex, mainwy in prefrontaw areas") by activation of KORs in dese areas is primariwy responsibwe for de profound consciousness-awtering/dissociative hawwucinogen effects of sawvinorin A and oder KOR agonists.[20][21] In addition, it has been stated dat "de subjective effects of S. divinorum indicate dat sawvia disrupts certain facets of consciousness much more dan de wargewy serotonergic hawwucinogen [LSD]", and it has been postuwated dat inhibition of a brain area dat is apparentwy as fundamentawwy invowved in consciousness and higher cognitive function as de cwaustrum may expwain dis.[20] However, dese concwusions are merewy tentative, as "[KORs] are not excwusive to de cwaustrum; dere is awso a fairwy high density of receptors wocated in de prefrontaw cortex, hippocampus, nucweus accumbens and putamen", and "disruptions to oder brain regions couwd awso expwain de consciousness-awtering effects [of sawvinorin A]".[21]

Theories suggest de cwaustrum may act to bind and integrate muwtisensory information, or ewse to encode sensory stimuwi as sawient or nonsawient (Madur, 2014). One deory suggests de cwaustrum harmonizes and coordinates activity in various parts of de cortex, weading to de seamwess integrated nature of subjective conscious experience (Crick and Koch, 2005; Stiefew et aw., 2014). Disrupting cwaustraw activity may wead to conscious experiences of disintegrated or unusuawwy bound sensory information, perhaps incwuding synesdesia. Such deories are in part corroborated by de fact dat [sawvia divinorum], which functions awmost excwusivewy on de KOR system, can cause consciousness to be decoupwed from externaw sensory input, weading to experiencing oder environments and wocations, perceiving oder “beings” besides dose actuawwy in de room, and forgetting onesewf and one’s body in de experience.[19]

The depressive-wike behaviors fowwowing prowonged morphine abstinence appear to be mediated by upreguwation of de KOR/dynorphin system in de nucweus accumbens, as de wocaw appwication of a KOR antagonist prevented de behaviors.[25] As such, KOR antagonists might be usefuw for de treatment of depressive symptoms associated wif opioid widdrawaw.[25]

Activation of de KOR appears to antagonize many of de effects of de MOR, incwuding anawgesia, towerance, euphoria, and memory reguwation, uh-hah-hah-hah.[26]Naworphine and nawmefene are duaw MOR antagonists and KOR agonists dat have been used cwinicawwy as antidotes for opioid overdose, awdough de specific rowe and significance of KOR activation in dis indication, if any, is uncertain, uh-hah-hah-hah. In any case however, KOR agonists notabwy do not affect respiratory drive, and hence do not reverse MOR activation-induced respiratory depression.[27]

Ewuxadowine is a peripherawwy restricted KOR agonist as weww as MOR agonist and DOR antagonist dat has been approved for de treatment of diarrhea-predominant irritabwe bowew syndrome. Asimadowine and fedotozine are sewective and simiwarwy peripherawwy restricted KOR agonists dat were awso investigated for de treatment of irritabwe bowew syndrome and reportedwy demonstrated at weast some efficacy for dis indication but were uwtimatewy never marketed.

KOR agonists are known for deir characteristic diuretic effects, due to deir negative reguwation of vasopressin, awso known as antidiuretic hormone (ADH).[28]

Found in numerous species of mint, (incwuding peppermint, spearmint, and watermint), de naturawwy-occurring compound mendow is a weak KOR agonist[55] owing to its antinociceptive, or pain bwocking, effects in rats. In addition, mints can desensitize a region drough de activation of TRPM8 receptors (de 'cowd'/mendow receptor).[56]

Used for de treatment of addiction in wimited countries, ibogaine has become an icon of addiction management among certain underground circwes. Despite its wack of addictive properties, ibogaine is wisted as a Scheduwe I compound in de US because it is a psychoactive substance, hence it is considered iwwegaw to possess under any circumstances. Ibogaine is awso a KOR agonist[59] and dis property may contribute to de drug's anti-addictive efficacy.

KOR agonists have recentwy been investigated for deir derapeutic potentiaw in de treatment of addiction[60] and evidence points towards dynorphin, de endogenous KOR agonist, to be de body's naturaw addiction controw mechanism.[61] Chiwdhood stress/abuse is a weww known predictor of drug abuse and is refwected in awterations of de MOR and KOR systems.[62] In experimentaw "addiction" modews de KOR has awso been shown to infwuence stress-induced rewapse to drug seeking behavior. For de drug-dependent individuaw, risk of rewapse is a major obstacwe to becoming drug-free. Recent reports demonstrated dat KORs are reqwired for stress-induced reinstatement of cocaine seeking.[63][64]

One area of de brain most strongwy associated wif addiction is de nucweus accumbens (NAcc) and striatum whiwe oder structures dat project to and from de NAcc awso pway a criticaw rowe. Though many oder changes occur, addiction is often characterized by de reduction of dopamine D2 receptors in de NAcc.[65] In addition to wow NAcc D2 binding,[66][67] cocaine is awso known to produce a variety of changes to de primate brain such as increases prodynorphin mRNA in caudate putamen (striatum) and decreases of de same in de hypodawamus whiwe de administration of a KOR agonist produced an opposite effect causing an increase in D2 receptors in de NAcc.[68]

Additionawwy, whiwe cocaine overdose victims showed a warge increase in KORs (doubwed) in de NAcc,[69] KOR agonist administration is shown to be effective in decreasing cocaine seeking and sewf-administration, uh-hah-hah-hah.[70] Furdermore, whiwe cocaine abuse is associated wif wowered prowactin response,[71] KOR activation causes a rewease in prowactin,[72] a hormone known for its important rowe in wearning, neuronaw pwasticity and myewination, uh-hah-hah-hah.[73]

It has awso been reported dat de KOR system is criticaw for stress-induced drug-seeking. In animaw modews, stress has been demonstrated to potentiate cocaine reward behavior in a kappa opioid-dependent manner.[74][75] These effects are wikewy caused by stress-induced drug craving dat reqwires activation of de KOR system. Awdough seemingwy paradoxicaw, it is weww known dat drug taking resuwts in a change from homeostasis to awwostasis. It has been suggested dat widdrawaw-induced dysphoria or stress-induced dysphoria may act as a driving force by which de individuaw seeks awweviation via drug taking.[76] The rewarding properties of drug are awtered, and it is cwear KOR activation fowwowing stress moduwates de vawence of drug to increase its rewarding properties and cause potentiation of reward behavior, or reinstatement to drug seeking. The stress-induced activation of KORs is wikewy due to muwtipwe signawing mechanisms. The effects of KOR agonism on dopamine systems are weww documented, and recent work awso impwicates de mitogen-activated protein kinase cascade and pCREB in KOR-dependent behaviors.[39][77]

Though cocaine abuse is a freqwentwy used modew of addiction, KOR agonists have very marked effects on aww types of addiction incwuding awcohow, cocaine and opiate abuse.[23] Not onwy are genetic differences in dynorphin receptor expression a marker for awcohow dependence but a singwe dose of a KOR antagonist markedwy increased awcohow consumption in wab animaws.[78] There are numerous studies dat refwect a reduction in sewf-administration of awcohow,[79] and heroin dependence has awso been shown to be effectivewy treated wif KOR agonism by reducing de immediate rewarding effects[80] and by causing de curative effect of up-reguwation (increased production) of MORs[81] dat have been down-reguwated during opioid abuse.

The anti-rewarding properties of KOR agonists are mediated drough bof wong-term and short-term effects. The immediate effect of KOR agonism weads to reduction of dopamine rewease in de NAcc during sewf-administration of cocaine[82] and over de wong term up-reguwates receptors dat have been down-reguwated during substance abuse such as de MOR and de D2 receptor. These receptors moduwate de rewease of oder neurochemicaws such as serotonin in de case of MOR agonists and acetywchowine in de case of D2. These changes can account for de physicaw and psychowogicaw remission of de padowogy of addiction, uh-hah-hah-hah. The wonger effects of KOR agonism (30 minutes or greater) have been winked to KOR-dependent stress-induced potentiation and reinstatement of drug seeking. It is hypodesized dat dese behaviors are mediated by KOR-dependent moduwation of dopamine, serotonin, or norepinephrine and/or via activation of downstream signaw transduction padways.